ABSTRACT The World Health Organization declared the Zika Virus (ZIKV) epidemic that began in Brazil in 2015 and rapidly spread to surrounding countries in the Americas and Caribbean an international public health emergency. The most concerning feature of this global epidemic, which is primarily being spread by the Aedes species of mosquitos, is its association with fetal brain damage in infants, manifesting as microcephaly and other neurologic deficits. Thus, it is a global priority to rapidly develop strategies for prevention of maternal infection, primarily a maternal ZIKV vaccine that can protect women from ZIKV infection and/or the associated fetal disease. Yet, the lack of understanding of the natural maternal immune responses to ZIKV infection and how they relate to fetal outcome will impede vaccine development. Virus-specific antibodies are often critical for protection against virus acquisition and are passed to the fetus during late pregnancy, yet pre-existing antibody responses against dengue virus, a predominant co-circulating flavivirus, can have detrimental effects on dengue disease pathogenesis via antibody-dependent enhancement (ADE). Thus, we hypothesize that the presence of cross-reactive maternal antibodies that can mediate ADE or placental cell transfer and the magnitude and potency of the ZIKV-specific maternal antibody response predict the severity of fetal ZIKV infection in a prospective, multi-national pregnancy cohort in Victoria, Brazil and Singapore, Singapore. We have assembled a global, highly skilled team with expertise in maternal-fetal viral infection, obstetric clinical trials, and immunology involving emerging infections and more specifically flaviviruses. Understanding the relationship between maternal antibody responses, in utero virus transmission, and fetal outcome is critical to defining the immunologic roadmap for a maternal ZIKV vaccine.